Balloon dilatation of the coronary arteries is a critically important modality in treating patients suffering from coronary artery disease. Although the initial success rate is over 90%, restenosis occurs in 25 to 50% of patients weeks or months following the procedure. Restenosis is due to activation of smooth muscle cells (SMC) that normally reside in the media: after they are injured by balloon angioplasty they proliferate and migrate to the subentema, such that they can lead to restenosis. We are involved in research aimed at developing therapy to prevent restenosis. In these studies we are using antisense olygodeoxynucleotides (ODNS) to selectively inhibit growth factors that cause SMC proliferation. Proteins are synthesized by translation of mRNA. The mRNA conveys a real message; ie. it contains the code for a specific protein. This is called the "sense" message. The sequence of nucleotides that are the exact compliment of the sense mRNA is called "antisense"--it does not encode a message that can be translated into a protein. The antisense sequence binds to the sense mRNA, thereby interfering with translation. Using rat aortic SMC, we have tested ODNS targeted to proliferating cell nuclear antigen (PCNA), a 36kDa nuclear protein expressed at high levels only when cells are rapidly proliferating. PCNA is a prerequisite for the induction of DNA replication. Our study demonstrates that proliferating rat SMCs are growth-inhibited by exogenously added ODNs targeted to rat PCNA in a dose-dependent fashion. Maximal inhibition is 50%. This study advances our understanding of the mechanisms responsible for SMC proliferation; and the results also suggest a novel approach to treating the clinical problem of restenosis.